Tetrahedron Letters 48 (2007) 1715–1719

An efficient and versatile route to the synthesis

of 9,10-dihydro-3-formylphenanthrenesI
Ramendra Pratap and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 20 November 2006; revised 2 January 2007; accepted 10 January 2007
Available online 14 January 2007

Abstract—An innovative and efficient route to the synthesis of 9,10-dihydro-3-formylphenanthrenes 7 has been delineated through
the ring transformation of 2-oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles 4 with methyl glyoxaldimethylac-
etal 5 to masked 3-dimethoxymethyl-1-sec-amino-9,10-dihydrophenanthrene-3-carbonitriles 6 followed by deacetalation with
Amberlyst 15 in excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.

The presence of a formyl group in a molecule makes it chloride in the presence of 5% Pd–BaSO4 catalyst in
highly versatile for generating molecular diversity very good yields. This route is also useful for the prepa-
through C–C and C–heteroatom bond formation.1 For- ration of 9-formyl phenanthrene, which has also been
myl derivatives are invariably used as ligands for the prepared14 by the reaction of phenanthrene and HCN
synthesis of metal chelates. They are also useful building as well as from the interaction of 9-phenanthrylmagne-
blocks for the construction of various synthetic and nat- sium bromide and ethyl orthoformate.
ural products of therapeutic importance. There are var-
ious ways to introduce a formyl group onto an aromatic The lack of a concise, straightforward protocol for the
ring. Among these protocols, Gatterman,2 Gatterman- construction of 9,10-dihydro-3-formylphenanthrene in-
Koch3 and Vilsmeier-Haack4 reactions are prominent. spired us to develop a novel, short and efficient synthesis
The use of formylating agents such as orthoformate,5 as an alternative to the former procedures.
formyl fluoride–BF36 and dichloromethyl ether–AlCl37
are alternative routes to the synthesis of formyl arenes. 2-Oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-
These are also obtained by oxidation of methyl or hy- 3-carbonitriles (4), which were used as synthons for the
droxy methyl arenes,8 or reduction of nitriles,9 amides10
and acid chlorides.11
SCH3
It was a great surprise to us that the chemistry of form- CN
O
ylphenanthrenes had not been explored significantly NC COOCH3
DMSO/KOH
after 1936. The synthesis of 1-formylphenanthrene has + O O
been reported12 from 1-phenanthranilide by conversion H3CS SCH3
R
6h
into imidoyl chloride followed by reduction with SnCl2 R
1 2 3
and HCl, while 2- and 3-formylphenanthrenes were pre- C2H5OH HNR1R2
pared13 by the hydrogenation of the corresponding acid
NR1R2
CN

Keywords: Tetralone; Formylphenanthrene; 2-Oxo-4-sec-amino-5,6- O O

dihydro-2H-benzo[h]chromene-3-carbonitriles; Masked aldehyde;
R
Ring transformation. 4
q
CDRI Communication No. 7079.
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 Scheme 1. Reaction showing the synthesis of 2-oxo-4-sec-amino-5,6-
2623405; e-mail: vjiram@yahoo.com dihydro-2H-benzo[h]chromene-3-carbonitriles.

0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.049
1716 R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719

Table 1. Duration of reaction and yields of the various 2-oxo-5,6- preparation of 9,10-dihydro-3-formylphenanthrenes
dihydrobenzo[h]chromenes were synthesized in two steps. The first step was the
Compound Structure Duration of Yields synthesis of 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-
reaction (h) (%) benzo[h]chromene-3-carbonitrile 3, from the reaction
of methyl 2-cyano-3,3-dimethylthioacrylate 1 and 1-tetr-
SCH3
CN
alone 2 in the presence of powdered KOH in DMSO.
3a 6 94
The second step was the amination of 3 with a sec-amine
O O in refluxing ethanol (Scheme 1 and Table 1).
SCH3 From the topography of 2-oxo-4-sec-amino-5,6-dihy-
CN
dro-2H-benzo[h]chromene-3-carbonitriles 4 it is evident
3b 6 82 that the C-2, C-4 and C-10b positions are electrophilic
O O
in nature. Position C-10b is highly susceptible to nucleo-
H3CO philic attack due to the extended conjugation and the
presence of an electron-withdrawing substituent at posi-
tion 3 of the chromene ring. The masked 9,10-dihydro-
N 3-formylphenanthrenes 6 were prepared by stirring an
4a CN 5.5 96 equimolar mixture of 4, methyl glyoxaldimethylacetal
5 and powdered KOH in dry DMF at room temperature
O O for 2.5–4 h, followed by pouring the reaction mixture
onto crushed ice with vigorous stirring. Neutralization
CH3 of the reaction mixture with 10% aqueous HCl provided
a precipitate, which was filtered, washed with water and
finally purified on a neutral alumina column and charac-
4b N 6.5 91 terized as the masked aldehydes 6 in 72–91% yield
CN (Scheme 2 and Table 2). There was also the possibility
of formation of (3-dimethoxymethyl-9,10-dihydro-2-
O O oxaphenanthrene-1-ylidene)acetonitrile by cyclization
involving the enolic OH and C-4 of the 2-
C6H5 oxobenzo[h]chromene through Michael addition fol-
lowed by elimination of the secondary amine. However,
under the applied reaction conditions no such product
was isolated possibly due to the presence of the elec-
4c N 7 81 tron-releasing acetal group, which did not facilitate
CN
enolization.
O O
The reaction was possibly initiated by the attack of a
carbanion, generated in situ from methyl glyoxaldime-
thylacetal 5 at C-10b with ring closure followed by
decarboxylation and dehydration to yield 6. The deace-
N
talation of 6 by Amberlyst 15 led to aldehyde 7 in high
4d 6 82 yields (Scheme 3 and Table 3).
CN

O O To the best of our knowledge, this is the first report on

the synthesis of functionalized 9,10-dihydro-3-formylph-
CH3 enanthrenes using 2-oxo-4-sec-amino-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitriles 4 as substrates for

N
4e 5.5 71 1 2
R RN
CN O O
NR1R2
5 4 O CN
3 CN
6 DMF/KOH
O O 2
OCH3 O
H3C
10b +
7
10a O O OCH3
H3CO 1 OCH3
R 8 10 5 OCH3
9
4
R
C6H5
1 2
1 2 R RN O O
N H3CO OCH3
R RN
CN CN
NC
OH OH
4f N 6 79
1 2 H OCH3 OCH3
CN R RN
OCH3 OCH3
R
6 R R
O O
Scheme 2.
 R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719 1717

Table 2. Duration of reaction and yields of the various masked 9,10- NR1R2
NR1R2
dihydro-3-formylphenanthrene aldehydes CN
CN
Compound Structure Duration of Yields
Amberlyst 15
reaction (h) (%) OCH3 CHO
CHCl3
OCH3 R
R
6 7
N
CN Scheme 3.
6a OCH3
3 84

OCH3
Table 3. Duration of reaction and yields of the various 9,10-dihydro-3-
formylphenanthrene aldehydes

CH3 Compound Structure Duration of Yields

reaction (h) (%)

6b N 2.5 72
CN N
7a CN 3 98
OCH3

OCH3 CHO

CH3

C6H5

7b N 2.5 99
CN
6c N 3 86
CN CHO

OCH3
C6H5
OCH3

7c N 3 97
CN

CHO
N
6d 4 76
CN

OCH3

OCH3
N
7d 4 99
CN

CH3
CHO
CH3
N
6e CN
3.5 91

OCH3 N
7e 3.5 99
CN
OCH3
H3CO
CHO

H3CO
C6H5
C6H5
N
N

6f N 2.5 87
CN 7f N 3.5 98
CN
OCH3

OCH3 CHO
1718 R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719

ring transformation reactions with methyl glyoxaldime- Synthesis of 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-

thylacetal 5. The synthetic strategy is very simple and benzo[h]chromene-3-carbonitrile (3a): Compound 3a was
straightforward. The yields were excellent without the obtained by stirring an equimolar mixture of methyl 2-
use of any catalyst. cyano-3,3-dimethylthioacrylate (0.05 mol, 10.15 g) and 1-
tetralone (0.05 mol, 7.3 mL) in the presence of powdered
KOH (0.06 mol, 3.4 g) in DMSO (50 mL) for 5–6 h.
All the compounds synthesized were characterized by Thereafter, the reaction mixture was poured onto crushed
spectroscopic techniques.15 This methodology provided ice with vigorous stirring. The precipitate was filtered,
a new avenue for the synthesis of congested 9,10-dihy- washed with water then dried and purified by crystalliza-
dro-3-formylphenanthrenes in excellent yields. tion from methanol. Yield: 94%; mp: 204–206 °C; IR
(KBr): 2922, 2370, 2207, 1699, 1612, 1570, 1508,
1446, 1372, 1279, 1257, 1221, 1155, 1132, 1092, 1037,
968, 900, 784, 742 cm 1; 1H NMR: (300 MHz, CDCl3): d
Acknowledgements 2.77–2.83 (m, 2H, CH2), 2.88–2.96 (m, 2H, CH2), 2.98 (s,
3H, SCH3), 7.23–7.27 (m, 1H, ArH), 7.31–7.44 (m, 2H,
V.J.R. and R.P. are thankful to the CSIR, New Delhi, ArH), 7.86–7.88 (m, 1H, ArH); 13C NMR (75 MHz,
for financial support. The authors also thank SAIF, CDCl3): d 16.26, 20.37, 25.56, 91.60, 110.89, 113.69,
CDRI, Lucknow, for providing spectroscopic data. 123.70, 125.19, 126.28, 126.69, 130.88, 137.01, 153.23,
157.07, 167.07; MS m/z 270 (M++1); HRMS: (EI, 70 eV)
calcd for C15H11NO2S 269.05105 (M+) found for m/z
269.05153.
References and notes Synthesis of 4-(piperidin-1-yl)-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile (4a): Compound 4a was
1. Mohata, P. K.; Kumar, U. K. S.; Sriram, V.; Illa, H.; prepared by refluxing a mixture of 3a (0.01 mol, 2.7 g) and
Junjappa, H. Tetrahedron 2003, 59, 2631. piperidine (0.012 mmol, 1.3 mL) in ethanol (50 mL) for
2. (a) Truce, W. E. Org. React. 1957, 9, 37; (b) Tanaka, M.; 5 h. The reaction mixture was cooled to room temperature
Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106; (c) and filtered. The resulting precipitate was crystallized from
Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, ethanol, yield: 96%; mp: 238–240 °C; IR (KBr): 2938,
113, 691. 2855, 2208, 1702, 1611, 1513, 1452, 1349, 1302, 1245, 1145,
3. (a) Toniolo, L.; Graziani, M. J. Organomet. Chem. 1095, 1049, 1003, 974, 939, 896, 760, 709 cm 1; 1H NMR:
1980, 194, 221; (b) Grounse, N. N. Org. React. 1949, 5, (300 MHz, CDCl3): d 1.76 (br s, 6H, CH2), 2.65–2.70 (m,
290. 2H, CH2), 2.86–2.91 (m, 2H, CH2), 3.51–3.53 (m, 4H,
4. (a) Blaser, D.; Calmes, M.; Daunis, J.; Natt, F.; Tardy- CH2), 7.21–7.24 (m, 1H, ArH), 7.30–7.41 (m, 2H, ArH),
Delassus, A.; Jacquier, R. Org. Prep. Proced. Int. 1993, 7.82–7.86 (m, 1H, ArH); MS m/z 307 (M++1); HRMS:
25, 338; (b) Jutz, C. Adv. Org. Chem. 1976, 9, 225; (c) (EI, 70 eV) calcd for C19H18N2O2 306.1360 (M+) found
Meth-Cohn, O.; Goon, S. J. Chem. Soc., Perkin Trans. 1 for m/z 306.1358.
1997, 85; (d) Kantlehner, W. Adv. Org. Chem. 1979, 9, 5; Synthesis of masked formylphenanthrenes (6): An equimo-
(e) Meth-Cohn, O.; Tarnowski, B. In Advances in lar mixture of 2-oxo-4-sec.amino-5,6-dihydro-2H-
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: benzo[h]chromene-3-carbonitrile (0.5 mmol), methyl gly-
New York, 1982; Vol. 31, pp 207–236; (f) Rudloff, I.; oxaldimethylacetal (0.5 mmol) and powdered KOH
Michalik, M.; Montero, A.; Peseke, K. Synthesis 2001, (0.7 mmol) in dry DMF was stirred at room temperature
1686. for 2–3 h. Thereafter, the reaction mixture was poured
5. Gross, S.; Rieche, A.; Matthey, G. Chem. Ber. 1963, 96, onto crushed ice with vigorous stirring. Neutralization
308. with 10% aqueous HCl gave a precipitate which was
6. Olah, G. A.; Kuhn, S. J. J. Am. Chem. Soc. 1960, 82, filtered, washed with water and purified by neutral
2380. alumina column chromatography using hexane:ethyl ace-
7. (a) Reiche, A.; Gross, H.; Hoft, E. Chem. Ber. 1960, 93, tate (99:1) as the eluent. Compound 6d: Yield: 76%; mp:
88; (b) Lewin, A. H.; Parker, S. R.; Fleming, N. B.; Carrol, 168–170 °C; IR (KBr): 2928,2838, 2367, 2341, 2219, 1658,
F. I. Org. Prep. Proced. Int. 1978, 10, 201. 1588, 1552, 1427, 1375, 1255, 1216, 1118, 1065, 971, 893,
8. Frey, L. F.; Marcantonio, K.; Frantz, D. E.; Murry, J. A.; 762 cm 1; 1H NMR: (300 MHz, CDCl3): 2.73–2.78 (m,
Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Tetra- 2H, CH2), 2.88 (br s, 2H, CH2), 3.04 (br s, 2H, CH2), 3.49
hedron Lett. 2001, 42, 6815. (s, 6H, OCH3), 3.65 (br s, 2H, CH2), 4.38 (br s, 2H, CH2),
9. Zilberman, E. N.; Pyryalova, P. S. J. Gen. Chem. USSR 5.65 (s, 1H, CH), 7.02–7.05 (m, 1H, ArH), 7.13–7.35 (m,
1963, 33, 3348. 6H, ArH), 7.78–7.81 (m, 1H, ArH), 7.87 (s, 1H, ArH);13C
10. (a) Zakharkin, L. I.; Khorlina, I. M. Bull. Acad. Sci. NMR: (75 MHz, CDCl3): 22.10, 27.07, 29.35, 47.40, 51.46,
USSR, Div. Chem. Sci. 1959, 2046; (b) Muraki, M.; 53.40, 100.98, 106.02, 115.02, 117.59, 123.66, 124.49,
Mukaiyama, T. Chem. Lett. 1975, 875; (c) Godjoian, G.; 124.88, 124.97, 125.90, 126.71, 127.60, 127.99, 132.41,
Singaram, B. Tetrahedron Lett. 1997, 38, 1717. 133.28, 133.40, 135.47, 136.62, 138.85, 140.10, 151.56; MS
11. (a) Cha, J. S.; Brown, H. C. J. Org. Chem. 1993, 58, 4732; m/z 411 (M++1); HRMS: (EI, 70 eV) calcd for
(b) Maier, W. F.; Chettle, S. J.; Rai, R. S.; Thomas, G. C27H26N2O2 410.1994 (M+) found for m/z 410.1988.
J. Am. Chem. Soc. 1986, 108, 2608. Synthesis of 3-formylphenanthrenes (7): These were
12. Bachmann, W. E.; Boatner, C. H. J. Am. Chem. Soc. 1936, obtained by stirring a solution of masked formylphe-
58, 2097. nanthrene 6 (0.2 mmol) in chloroform with Amberlyst 15
13. Mosettig, E.; van de Kamp, J. J. Am. Chem. Soc. 1933, 55, for 2.5–4 h. The progress of the reaction was monitored by
2995. TLC. After completion, the reaction mixture was filtered
14. Miller, H. F.; Bachman, G. B. J. Am. Chem. Soc. 1935, 57, and the solvent was removed under reduced pressure. The
766. solid obtained was crystallized from chloroform:methanol
15. Representative procedure for the synthesis of 2-oxo-4-sec- (1:1). Compound 7e: Yield: 99%; mp: 164–166 °C; IR
amino-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles (4): (KBr): 2923, 2848, 2362, 2219, 1698, 1593, 1430, 1384,
 R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719 1719

1353, 1220, 1152, 1101, 1055, 972, 900, 838, 758, 700 cm 1; 2.58 Hz, 1H, ArH), 7.71 (d, J = 8.61 Hz, 1H, ArH), 8.02
1
H NMR: (300 MHz, CDCl3): 1.01 (d, J = 6.3 Hz, 3H, (s, 1H, ArH), 10.36 (s, 1H, CHO); 13C NMR: (75 MHz,
CH3), 1.41–1.44 (m, 1H, CH), 1.61–1.64 (m, 2H, CH2), CDCl3): 20.87, 27.18, 28.42, 29.27, 33.83, 50.15, 54.11,
1.73–1.77 (m, 2H, CH2), 2.81 (t, J = 6.69 Hz, 2H, CH2), 111.55, 112.08, 118.25, 124.60, 125.26, 135.08, 138.10,
2.94 (t, J = 6.48 Hz, 2H, CH2), 3.13–3.16 (m, 2H, CH2), 139.29, 140.10, 153.67, 159.29, 188.30; MS m/z 361
3.40–3.44 (m, 2H, CH2), 3.86 (s, 3H, OCH3), 6.81 (d, (M++1); HRMS: (EI, 70 eV) calcd for C23H24N2O2
J = 2.4 Hz, 1H, ArH), 6.87 and 6.89 (dd, J = 2.58 and 360.1837 (M+) found for m/z 360.1843.